M104 T3 L3 Flashcards
Which arteriole in the kidney is narrower?
the efferent arteriole
Why it is useful that the afferent arteriole in the kidney is narrower?
it causes a pressure to build up in the nephrons
What is the difference between the afferent and efferent arterioles in the kidneys?
afferent - blood travels in and is filtered under-pressure
efferent - exit
What is an effect of the afferent arteriole in the kidney being narrower?
blood traveling in through it is filtered under-pressure, so it can’t leave as easily
What is the pressure that builds up due to the narrowing of the efferent arteriole?
10 mmHg
What two features is filtration force in the nephrons determined by?
Blood pressure
Differing diameter of afferent and efferent arterioles
What is the normal Glomerular Filtration Rate of all the glomerulae in the kidneys?
125 mL/min (180 L/day)
What is the normal plasma volume?
2-3 L
What is the Glomerular Filtration Rate used to indicate?
renal function when measured clinically
What small molecules are filtered in ultrafiltration?
Glucose, electrolytes, metabolites (GEM)
Some drugs, amacs, Metabolic waste (SAM)
What is the first stage of filtration?
Ultrafiltration
What substances remain in the blood after ultrafiltration?
RBCs, lipids, proteins, most drugs, metabolites
What barriers does filtrate have to pass through?
the glomerular capillary endothelium via small pores
the basement membrane of Bowman’s capsule
(includes contractile mesangial cells)
podocytes via filtration slits into capsular space
What is the diameter of the pores in the endothelium of the glomerular capillary?
60um
What is the effect of the contractile properties of mesangial cells?
they have been shown to be insignificant in changing the filtration pressure of the glomerulus
What structures interdigitate with themselves?
pedicels - they join together but they have small gaps between them
What structure results from the gaps between interdigitated pedicels?
filtration slits
What is the role of filtration slits?
they allow molecules to come through the pedicels
Why are podocytes susceptible to damage?
bc they are very specialized and very sensitive cells
When might podocytes be damaged?
certain renal diseases, e.g. diabetes
How can diabetes damage podocytes?
a high glucose level in circulation is filtered through podocytes during the filtration process
podocytes get poisoned by high glucose
this leaves gaps in the glomerular membrane, which allows proteins to leak through
What happens to podocytes when exposed to high glucose levels?
they get poisoned and can die, break off and come out into the urine
Where is the glomerular membrane located?
at the top of the nephrons
What happens to diabetics as kidney disease gets worse?
more and more podocytes die off and aren’t replaced
What happens as a result of podocytes dying off?
Albuminuria from protein urea in the urine
How often are urine protein amounts measured in diabetic patients?
every six months
What is it an indication of if a diabetic patient’s protein levels start to increase?
that some kidney disease is developing
How is the PGC calculated?
normal body BP + extra pressure from the narrow efferent arteriole
What does PGC measure?
the hydrostatic pressure of blood in the glomerular capillary
How does oncotic pressure work?
circulatory proteins (mostly albumin) in blood plasma exert oncotic pressure this displaces water molecules, creating a relative h2o mlc deficit with water molecules moving back into the circulatory system within the lower venous pressure end of capillaries
Why is oncotic pressure higher in the glomerular capillary than in Bowman’s capsule?
bc there is lots of albumin which gets left behind and doesn’t get filtered
Why is the oncotic pressure of the Bowmans capsule almost zero?
bc there are hardly any proteins in the top of the nephron bc in healthy people the proteins don’t leak through
What is the main glomerular pressure?
the pressure of the blood coming through when the glomerular capillaries push fluids through
What is the equation of filtration pressure?
(PGC + πBS) – (PBS + πGC)
What four factors contribute to filtration pressure?
PGC
πBS
PBS
πGC
What is the equation of filtration pressure when oncotic pressure is nearly equal to zero?
PGC – (PBS + πGC)
What is the hydrostatic pressure in a nephron?
45 mmHg
What is the osmotic pressure in a nephron?
25 mmHg
What is the hydrostatic pressure in a nephron?
10 mmHg
What is the net filtration pressure in a nephron?
10 mmHg
What is the net filtration pressure in a nephron calculated?
45 - 25 - 10 = 10 mmHg
How is filtration pressure calculated?
(PGC + πBS) – (PBS + πGC)
the bp in the glomerular capillaries minus the two pressures pushing back the other way against it
What is normal bp?
120 / 80
What is the rate at which filtrate is produced in the kidneys?
125 mL/min (180 L/day)
What happens to the GFR and renal blood flow as circulatory bp changes?
they stay quite constant
What happens to the GFR and renal blood flow as systemic bp changes?
they stay quite constant via autoregulation
Over what range of systemic bps is GFR and renal blood flow under autoregulation?
broad range of 90-200 mmHg
In what circumstances will the NS in the kidneys be impaired?
if the NS (renal nerve) has been removed
isolated perfuse kidneys
in conditions where the renal nerve has been removed / damaged
What is the autoregulation of GFR and renal blood flow NOT controlled by and why?
the NS bc in kidneys where the NS is impaired / removed, autoregulation still occurs
neuronal or hormonal bc the autoregulation doesn’t respond to any hormones circulating in the blood system
In what circumstances will the NS in the kidneys be impaired?
if the NS (renal nerve) has been removed
isolated perfuse kidneys
in conditions where the renal nerve has been removed / damaged
How is the autoregulation of GFR and renal blood flow established in the kidneys?
the kidney has a way of adjusting its blood system and the diameter of the renal artery according to the body’s bp to ensure that it keeps getting the same blood flow, even if the body’s bp is changing in a particular way
What are the two hypotheses that explain how the GFR and renal blood flow is autoregulated?
Myogenic
Metabolic
What does the Myogenic hypotheses state?
that the autoregulation of GFR and renal blood flow is due to response of renal arterioles to stretch (Frank–Starling law of the heart)
What happens to the renal artery and efferent arterioles when bp decreases, according to the Myogenic hypotheses?
they automatically constrict to maintain a constant renal blood flow and GFR
What does the Metabolic hypotheses state?
that afferent & efferent arteriolar contraction / dilation is modulated by renal metabolites
What is the constant renal blood flow?
1200mL/min
What is the GFR?
~125 mL/min
What are examples of renal metabolites that involved in the Metabolic hypotheses?
adenosine, nitric oxide
What is the likely way in which the GFR and renal blood flow is autoregulated?
Most likely to be a combination of both hypotheses (metabolic & myogenic)
What happens to the autoregulation of the GFR and renal blood flow below the range of 90-200 mmHg?
the system breaks down and renal function declines
What happens to the autoregulation of the GFR and renal blood flow above the range of 90-200 mmHg?
renal function goes out of control and can damage internal renal structures, causing blood loss and damage within the kidney structures
What substances is natriuresis is promoted by?
ventricular and atrial natriuretic peptides
calcitonin
What is an example of a substance natriuresis is inhibited by?
aldosterone
Where is atrial natriuretic peptide secreted from?
the atria
What is the main function of atrial natriuretic peptide?
reduces ECF volume by increasing renal sodium excretion
How do kinins affect the circulatory system?
they affect bp pressure (especially low bp)
they increase blood flow throughout the body
they make it easier for fluids to pass through small blood vessels
What happens to inflow blood (via the afferent arteriole) when the GFR is low?
specific vasodilators are released, the afferent artery dilates
Angiotensin II is released, the efferent artery constricts
Where is atrial natriuretic peptide secreted from?
the atria
What is the main function of atrial natriuretic peptide?
reduces ECF volume by increasing renal sodium excretion
How do kinins affect the circulatory system?
they affect bp (especially low bp)
they increase blood flow throughout the body
they make it easier for fluids to pass through small blood vessels
Afferent arteriole
GFR
e.g. due to BP
What vasodilators are released when the GFR is low? (PAKD.NO)
Prostaglandins, ANP, kinins, dopamine, NO
What happens to outflow blood (via the efferent arteriole) when the GFR is high?
specific vasoconstrictors are released, the afferent artery constricts
adenosine & NO are released, the efferent artery dilates
What vasoconstrictors are released when the GFR is high?
noradrenaline , endothelin, adenosine (via A1 receptors), ADH
What receptors are responsible for the release of adenosine as a vasoconstrictor?
A1 receptors
What nerves are responsible for the release of noradrenaline?
the sympathetic nerves
What receptors are responsible for the release of adenosine as a vasodilator?
A2A & A2B receptors
How does a drop in the GFR alter the systemic bp and how is the GFR affected after?
AAR, less Na+ enters the proximal tubule
the macula densa senses a change in tubular Na+ levels
stimulates juxtaglomerular cells to release renin into the blood, which makes angiotensinogen, is converted to angiotensin I
goes to the lungs via circulation where ACE is present
gets converted to Ang II
acts as a vasoconstrictor, pushes up the BP, causes filtration pressure to increase
GFR returns to normal
What causes a drop in GFR?
a drop in filtration pressure (e.g. due to declining BP)
What are juxtaglomerular cells otherwise known as?
JG cells
granular cells
What is the function of juxtaglomerular cells?
to synthesize, store, and secrete renin. They are (and some in the efferent arterioles) that deliver blood to the glomerulus.
Where are juxtaglomerular cells located?
in the kidney, mainly in the walls of the afferent arterioles
What is the effect of a drop in the GFR on the systemic bp?
it increases due to Ang II and vasoconstriction
What process is responsible for enacting negative feedback when there is a drop in the GFR?
the Renin-Angiotensin System
What are features of angiotensin II?
is an extremely active, and a very small molecule
is very powerful bc it has lots of effects that increase the bp
How does angiotensin II act as a vasoconstrictor?
it acts on the symp NS so that the symp nerves release more adr
How does Ang II increase reabsorption of Na+ and water in the kidneys?
it increases Na+ reabsorption, so more salt re-enters the circulation
this causes water to re-enter the circulation from glomerular filtrate that builds up the circulating volume
this pushes bp up
makes the adrenal gland release aldosterone which also causes Na+ reabsorbtion, etc, further pushes bp up
AAR, the pituitary gland releases AHD, which further encourages reabsorption in the kidneys
Na+ reabsorption < water reabsorption < bp up < aldosterone (adrenal gland) < more reabsorption < ADH (pituitary gland) < more reabsorption
What is the effect of angiotensin II on thirst?
it works in the brain to increase thirst
results in drinking more fluids, which will enter your circulation and have a long term effect of bringing bp back up towards normal
What is the effect of hypertension on the RAAS system?
can cause it to become disregulated, overstimulated
Why does hypertension overstimulate the RAAS system?
bc the sympathetic NS is triggered all over the body and within the kidney, which causes more renin to be released and it kicks off the whole system of generating too much angiotensin
What does ARB stand for?
angiotensin 2 receptor blockers
What are examples of ACE inhibitor drugs that can be used to stop hypertension overstimulating the RAAS system?
captopril and enalapril (-pril drugs)
What is the role of ACE inhibitor drugs?
they inhibit angiotensin converting enzymes in the lungs
What are examples of ARB drugs that can be used to stop hypertension overstimulating the RAAS system?
sartan drugs like losartan
What is the effect of sartan drugs?
they act as antagonists on the AT1 receptor - the receptors that Angiotensin 2 works on
What is the receptor of Ang II?
AT1 receptor
What type of drugs are most drug names that end in –pril?
ACE inhibitors
What groups of drugs are used to stop hypertension from overstimulating the RAAS system?
ACE inhibitors (-pril) kiren drugs ARB drugs (sartans)
How do kiren drugs work?
they are renin inhibitors
What is an example of a kiren drugs that can be used to stop hypertension overstimulating the RAAS system?
aliskiren
What is behind the driving force of reabsorption from the proximal tubule?
Na+K+ATPase
What substances is there almost complete reabsorption of in the PT?
glucose, amacs, small amount of filtered Proteins (GAP)
What substances is there almost complete reabsorption of in the PT?
glucose, amacs, small amount of filtered Proteins (GAP)
What is the role of Na+-K+-ATPase?
to pump out Na+ from cells into the blood against chemical and electrical gradients
What does Na+-K+-ATPase require to work?
E - ATP
How does Na+-K+-ATPase work?
Na+ leaves the cell with Cl- (salt)
K+ enters with ATP
What is the ratio of transport of Na:K in and out of the cell via Na+-K+-ATPase?
3 Na+ leaves, 2 K+ enters
What is the intracellular Na+ concentration in PT cells?
less than 30 mM (very low)
Why is the intracellular Na+ concentration in PT cells really low?
due to the action of the Na+K+ATPase
What is the relationship between Na+-K+-ATPase and water movement?
Na+ leaves the cell with Cl- (salt) to enter the peritubular capillaries
water likes to follow the salt bc of the high conc of salt outside of the cells, so it gets dragged through aquaporins and makes it more dilute
What substances travel through Na+/glucose co-transporters and where to?
glucose travels with sodium into the cell
What are features of the Na+/glucose co-transporters?
it works all the time and is very powerful
What is the role of the Na+/glucose co-transporters?
to keep the inside of the proximal tubular cell at a low Na+ conc - at less than 30 mM instead of 150 mM around the glomerular filtrate site
What happens when the inside of the proximal tubular cell has a lower Na+ conc?
all the filtered sodium coming through from the glomerulus wants to enter the cells bc they have a low concentration
How does Na in the inside of the proximal tubular cell leave?
it is pumped out into the peritubular capillary from the base / the lateral side of the pump
How does Na enter the inside of the proximal tubular cell when it has a lower Na+ conc than the glomerular filtrate?
via a detraction conc grad
via an electrochemical gradient
Why are proximal tubular cells so negative?
bc it is packed full of -vely charged transport proteins that also make up the mitochondria
What is the overall charge in proximal tubular cells?
-70 mV
What is the overall charge in glomerular filtrate and why?
the overall charge is +ve bc Na+ is a positive ion and there’s lots of it in the glomerular filtrate
How does Na enter the proximal tubular cells against its conc grad from the glomerular filtrate via an electrochemical gradient?
the prox. tubular cells are -70mV but glomerular filtrate is positive - opposites attract
Where are aquaporin channels located?
on the apical and basolateral surfaces of the kidney cells
What does the movement of solutes (Na+, HCO3-
and Cl-) from glomerular filtrate into the proximal tubular cells achieve?
it reduces osmolality of tubular fluid and increases osmolality of interstitial fluid
By what routes does the net flow of water from the tubule lumen to lateral spaces occur?
transcellular and paracellular routes
What are features of the transcellular routes by which water flows from the tubule lumen to lateral spaces?
aquaporin channels
How is water reabsorbed along the nephron?
osmosis / follows Na+
How many different types of aquaporins have been identified?
thirteen
How many different types of aquaporins are present in the kidney?
six
What are the four major renal types of aquaporins?
AQP1, AQP2, AQP3 & AQP4
Where are Aquaporin-1s located?
they have an abundant distribution in the proximal tubule, and other parts of the tubule where water is reabsorbed, e.g. descending limb of LOH
Where are Aquaporin-2s located?
in the collecting duct on the apical surface
What substance is AQP-2 channel expression controlled by?
antidiuretic hormone
according to how dehydrated the person is
Where are Aquaporin-3s & 4s located?
on the basolateral surface of tubular cells involved in water reabsorption
How is glucose reabsorbed into the peritubular capillary?
via a glucose transporter
Why is there a low concentration of glucose in the peritubular capillary?
bc it has been filtered up the glomerulus
Once in the peritubular capillary, how does glucose re-enter the blood?
via a Na co-transporter
What percentage of available glucose is reabsorbed via the SGLT2 cotransporter in S1?
90% bc the body needs that glucose
What are the two parts of the proximal tubule?
the PCT & the proximal straight tubule PST
What transporters are responsible for the movement of glucose in Segment 1?
SGLT2, cotransports Na+ with glucose into the cell
What is S1 otherwise known as?
segment 1
the proximal convoluted tubule (PCT)
What is a feature of the SGLT2 cotransporter?
a very powerful pump
What makes the SGLT2 cotransporter a very powerful pump?
it has a low affinity and a high capacity
so it only needs small amounts of Na+ to transport a large amount of glucose
What percentage of available glucose is left behind from the SGLT2 cotransporter in S1?
10%
What happens to the left over glucose (10%) that is not reabsorbed by the SGLT2 cotransporter in S1?
it’s caught lower down in Segment 3, which has SGLT1 transporters
What is a feature of the SGLT2 cotransporter?
high affinity, low capacity
Where are the SGLT2 cotransporters located?
in Segment 1 / the PCT
Where are the SGLT1 cotransporters located?
in Segment 3 / the PST
What percentage of available glucose is reabsorbed in total?
100% bc the body needs that glucose
What substances are transported by the SGLT2 cotransporter?
Na+ is transported with one glucose
How much glucose is excreted in urine in healthy people?
very little
What happens if a diabetic patient has excessive glucose in their circulation?
when undergoing filtering in the proximal tubules, the SGLT transporters will get filled up to their maximum limit for transportation and so will be working at full capacity - their transport maximum
however, often, it is not enough to reabsorb all the glucose that’s being filtered in higher amounts (due to diabetes)
What is the normal plasma glucose concentration range in healthy patients?
5-10mM (5 or 6mM)
What percentage of plasma glucose is reabsorbed up to about 10 mM?
100% - almost all
How high will the plasma glucose concentration increase to after a sugary meal / drink?
up to about 10 mM
What is the approximate plasma glucose concentration range in diabetic patients after a sugary meal?
20-30 mM
What happens when plasma glucose concentration levels reach 20-30 mM after a sugary meal?
glucose transportation reaches a limit and discontinues, so glucose starts to appear in urine
How do blood urine tests work?
a dipstick is used to look at glucose urine levels
How is diabetes diagnosed?
blood urine tests will pick up any glucose in the patient’s urine
What does a blood urine test that does not detect any diabetes in the urine indicate?
that the patient is healthy
What is the long-term effect of diabetics continually excreting glucose?
it will eventually bring the blood glucose levels down, bc if glucose is continually excreted, it will eventually leave the body, having a beneficial effect - hypoglycaemic effect
What are examples of drugs used to treat diabetes?
biguanides (metformin only)
insulin injections
How do the biguanide drugs work?
by reducing the production of glucose that occurs during digestion
What is the only biguanide currently available in most countries for treating diabetes?
Metformin
Is Metformin a short or long term treatment of diabetes?
it needs to be taken long-term (years)
Does metformin have any side-effects?
mild and serious side effects, which are the same in men and women
What are examples of metformin side-effects?
diarrhoea, flatulence stomach pain, nausea, vomiting bloating, heartburn gas diarrhoea constipation weight loss
Where does glucose transport / reabsorption occur?
in the proximal tubules
What is an example of a drug that was previously used to treat diabetes II?
phlorizin
How does phlorizin work?
they accessed / got into the glomerular filtrate and were secreted into the proximal tubule where they would block thee Na/glucose transporters
How does phlorizin work?
they accessed / got into the glomerular filtrate and were secreted into the proximal tubule where they would block thee Na/glucose transporters in the proximal tubular cells so that this glucose couldn’t be absorbed and would come out in the urine
What class of drugs have been developed to treat diabetes II?
the flozin drugs
What are the three main flozins used in the West to treat diabetes II?
Dapagliflozin
Canagliflozin
Empagliflozin (BI-10773)
What type of drugs are the flozins?
SGLT2 inhibitors
What is the main flozin used in Japan to treat diabetes II?
Empagliflozin
How do flozins work?
they block the SGLT2 transporters in the kidneys to stop the glucose being reabsorbed so that glucose comes out in the urine and not so much enters the blood (which is the goal)
Which developmental diabetes drug was withdrawn/cancelled?
sotagliflozin
Why was sotagliflozin withdrawn / cancelled?
bc it caused liver toxicity in clinical trials
Why is having sugary urine potentially dangerous?
bc it makes patients more susceptible to UTIs bc bugs
like sugary solutions
Why are SGLT2 inhibitors used even though having sugary urine is potentially dangerous?
bc the benefits of these drugs seem to outweigh the risk of UTIs
bc any UTIs can be treated with antibiotics and good personal hygiene
bc it’s not normally a problem
Why are SGLT2 inhibitors potentially dangerous?
bc their aim is to cause sugary urine which can lead to UTIs sometimes
bc it can be misused by healthy people illegally was a way to lose weight
What are alternative uses of SGLT2 inhibitors?
they can be used to lose weight - can be abused, bc if glucose is removed from the system in healthy people, it won’t be converted to fat etc and will result in weight loss
Why are SGLT2 inhibitors dangerous to use for weight loss?
it leads to hypoglycaemia if used in healthy people or if misused - this can cause real issues of brain glucose loss that can lead to coma
Why are SGLT2 inhibitors potentially not very effective independently?
bc it elicits an adaptive increase in E intake - e.g. increased appetite
Why are SGLT2 inhibitors a very popular treatment for diabetes II internationally?
bc they have actually been shown to help diabetic patients avoid diabetic complications in clinical trials, bc they seem to make the patients healthier
What are the effects of SGLT2 inhibitors on diabetes II patients in clinical trials?
they don’t get as much kidney problems
they don’t get as much eye retinopathy
their CVS profiles are much better
What percentage of urea is reabsorbed in the proximal tubule?
about 40 - 50%
How are amacs transported in and around the proximal tubule?
via their independent transport system that involves endocytosis - proteins leak through from the glomerulus, so small amounts of proteins can be reabsorbed
How does endocytosis allow for the transportation of amacs?
the amacs have contact with the proximal tubular cell surface and enter it
then, as they travel through the proximal tube, they are broken down into amacs, which then are returned to the blood
What kinds of substances can’t be filtered at the glomerulus?
some endogenous substances and drugs
Why can’t some substances be filtered at the glomerulus?
bc of their size or protein binding
What two alternative specialised pumps are present in the PT?
one for organic acids
one for organic bases
What are examples of substances that are transported by the organic acid pump in the PT?
uric acid, diuretics, antibiotics (penicillin)
What are examples of substances that are transported by the organic base pump in the PT?
creatinine, procainamide
In what areas of the body is OAT1 present? (PEKS.BPTC)
placenta, eyes, kidneys, smooth muscles
brain, proximal tubular cells
What do the OAT1s control the excretion of?
common drugs, toxins, and endogenous metabolites into the urine
What is the role of URAT1?
a type of OAT located in renal PTCs, where it mediates the re-absorption of uric acid from the PT
What is the relationship between Na+ and a-KG?
when there is a low Na+ conc, it drags in alpha-ketaglutarate, which then is excreted by OAT pumps, which then drags in organic acid anions
What is the use of Para-aminohippurate?
a tool to measure tubular secretion
How is Para-aminohippurate processed before use?
it is IV infused
Is Para-aminohippurate produced by the body naturally?
no - it’s an endogenous compound
How is it that PAH can be used as a marker of tubular secretion?
bc it’s not filtered, it’s only secreted into the PT and is transported
What is the pathway of Para-aminohippurate after administration?
it is transported into PT cells from blood with a-Kg / other di/tri carboxylates
is it then transported out of PT cells in exchange for another anion present in the PT lumen
How is it a result on PAH used after administration?
after administration, the amount that comes out in the urine is measured
What is the main setting where PAH is used?
in a clinical setting
In what circumstances might PAH be used?
when we want to measure how much of a drug is being transported out at the same time
a ratio is made and compared between the ratio for the excretion of the drug to the excretion / secretion of PAH
What are examples of endogenous organic acids that are secreted into urine by the PT? (COPP.HHUBs)
cAMP Oxalate Procainamide Prostaglandins Hippurates (not PAH - synthetic) Hydrochlorothiazide Urate (Uric acid) Bile salts
What are examples of organic acid drugs that are secreted into urine by the PT? (CABS. FPPP)
Chlorothiazide Acetozolamide Bumetanide Salicylate (Aspirin) Furosemide Penicillin Probencid PAH
What are examples of endogenous organic bases that are secreted into urine by the PT? (ACD,GHNT)
Adrenaline (Epinephrine) Creatinine, Choline Dopamine Guanidine Histamine Noradrenaline (Norepinephrine) Thiamine
What are examples of organic base drugs that are secreted into urine by the PT? (MAP.QICA)
Morphine Atropine Procainamide Quinine Isoproterenol Cimetidine Amiloride
What is the overexpression of AT1 receptors associated with?
risk factors such as hypertension, hypercholesterolae- mia, and diabetes
What happens when there’s a drop in the GFR?
RAS is activated and is responsible for enacting negative feedback to increase the GFR back to normal levels
What substance does angiotensin stimulate the release of?
aldosterone
From where is aldosterone released?
the adrenal cortex
Why does angiotensin stimulate aldosterone release?
to promote sodium retention by the kidneys
